Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Tongguanteng injection induces cell cycle arrest and drives ferroptosis through AURKA/KEAP1/NRF2 axis in breast cancer.
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Liang Hanlu, Ding Qixuan, Chen Jiayi, Zhao Shuai, Zhou Yangyun, Hu Yujie, Xu Lingyan, Shi Meizhi, Yang Jiao, Zhang Xiangqi, Zhang Jingxian, Guo Cheng, Han Yonglong, Chen Junjun
Аннотация
BACKGROUND: Tongguanteng Injection (TGT), derived from the stems of Marsdenia tenacissima, has been demonstrated to exert anti-tumor effects. Aurora Kinase A (AURKA) is a key regulator of cell cycle progression and has become a promising target for breast cancer treatment. However, the role of AURKA in ferroptosis is unclear, particularly regarding its contribution to the therapeutic effect of TGT in breast cancer.
METHODS: The chemical components of TGT were analyzed by Ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). The anti-breast cancer effect of TGT were detected in vitro and in vivo. RNA-seq analysis were used to identify the targets of TGT treatment. Subsequently, flow cytometry, RT-PCR, western blot, Co-IP, immunofluorescence and immunohistochemistry were employed to elucidate the regulatory mechanisms of TGT on ferroptosis and cell cycle. Concurrently, ferroptosis and cell cycle associated pathways were investigated in the plasmids and siRNAs transfected cells. Furthermore, tumor bearing mouse model was established by 4T1 cells stably transduced with lentivirus for further validating the findings.
RESULTS: A total of 136 compounds were identified from TGT. The study demonstrates that TGT exerts an anti-breast cancer effect by inducing G2/M phase arrest and ferroptosis, evidenced by downregulation of CDK1 and Cyclin B, as well as increased Fe2+ accumulation, glutathione (GSH) depletion, and elevated lipid peroxidation. RNA-seq analysis revealed that AURKA was significantly downregulated and identified as a key target of TGT treatment. Mechanistically, TGT disrupts the AURKA-Kelch-like ECH-associated protein 1 (KEAP1) interaction, leading to nuclear factor E2-related factor 2 (NRF2) nuclear translocation and subsequent heme oxygenase 1 (HO-1)-mediated ferroptosis in vitro. Knockdown of AURKA or treatment with its inhibitor alisertib both induce G2/M phase arrest and ferroptosis, while AURKA overexpression reverses the effects of TGT and accelerates tumor progression. Combining TGT with docetaxel enhances ferroptosis sensitivity and amplifies the regulatory effect of AURKA on cell cycle and ferroptosis. Consistent with in vitro results, TGT significantly inhibited tumor growth, arrested cell cycle and promoted ferroptosis in 4T1-AURKALV cell bearing mice.
CONCLUSION: These findings propose that TGT targets AURKA/KEAP1/NRF2 axis to exert anti-breast cancer effect, and AURKA inhibition represents a potential strategy for breast cancer treatment through inducing cell cycle arrest and driving ferroptosis.
METHODS: The chemical components of TGT were analyzed by Ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). The anti-breast cancer effect of TGT were detected in vitro and in vivo. RNA-seq analysis were used to identify the targets of TGT treatment. Subsequently, flow cytometry, RT-PCR, western blot, Co-IP, immunofluorescence and immunohistochemistry were employed to elucidate the regulatory mechanisms of TGT on ferroptosis and cell cycle. Concurrently, ferroptosis and cell cycle associated pathways were investigated in the plasmids and siRNAs transfected cells. Furthermore, tumor bearing mouse model was established by 4T1 cells stably transduced with lentivirus for further validating the findings.
RESULTS: A total of 136 compounds were identified from TGT. The study demonstrates that TGT exerts an anti-breast cancer effect by inducing G2/M phase arrest and ferroptosis, evidenced by downregulation of CDK1 and Cyclin B, as well as increased Fe2+ accumulation, glutathione (GSH) depletion, and elevated lipid peroxidation. RNA-seq analysis revealed that AURKA was significantly downregulated and identified as a key target of TGT treatment. Mechanistically, TGT disrupts the AURKA-Kelch-like ECH-associated protein 1 (KEAP1) interaction, leading to nuclear factor E2-related factor 2 (NRF2) nuclear translocation and subsequent heme oxygenase 1 (HO-1)-mediated ferroptosis in vitro. Knockdown of AURKA or treatment with its inhibitor alisertib both induce G2/M phase arrest and ferroptosis, while AURKA overexpression reverses the effects of TGT and accelerates tumor progression. Combining TGT with docetaxel enhances ferroptosis sensitivity and amplifies the regulatory effect of AURKA on cell cycle and ferroptosis. Consistent with in vitro results, TGT significantly inhibited tumor growth, arrested cell cycle and promoted ferroptosis in 4T1-AURKALV cell bearing mice.
CONCLUSION: These findings propose that TGT targets AURKA/KEAP1/NRF2 axis to exert anti-breast cancer effect, and AURKA inhibition represents a potential strategy for breast cancer treatment through inducing cell cycle arrest and driving ferroptosis.